BackgroundAntibiotic-associated diarrhea (AAD) and Clostridium difficile disease (CDD) are common conditions linked to the use of antibiotics. Studies evaluating the efficacy of probiotics for the treatment of these two conditions have produced contradictory results.

ObjectivesTo determine the efficacy and safety of probiotics for the prevention of AAD and CDD.

Design and InterventionThe databases of PubMed, MEDLINE, Google Scholar, metaRegister, the NIH registry of clinical trials, and the Cochrane Central Register of Controlled Trials were searched to identify studies suitable for inclusion in the meta-analysis. In addition, reference lists, commentaries, books, and meeting abstracts were examined. Keywords, including "probiotics", "Clostridium difficile", "antibiotics", "diarrhea", "Saccharomyces", and "Lactobacilli" were used to carry out the search. Studies were eligible for inclusion if they were published between 1977 and 2005 in peer-reviewed publications, used human subjects, and were randomized controlled trials (RCTs) that examined efficacy. Exclusion criteria included case reports, Phase I safety studies, and trials that used unspecified probiotics. Diarrhea was defined as loose stools within 24 h for 2 days, or loose stools within 48 h. AAD was defined as diarrhea within 2 months of exposure to antibiotics. CDD was defined as diarrhea associated with a positive Clostridium difficile culture or toxin within a month of exposure to antibiotics. The quality of suitable studies was assessed according to a number of factors, including study design, sample size, and outcome measures. A quality grade was given to each study: 1 = poor, 2 = fair, 3 = good.

Outcome MeasureThe main outcome measure was identification of studies suitable for inclusion in the meta-analysis.

ResultsIn total, 31 RCTs were included in the meta-analysis, and all were rated fair or good quality. Of these, 25 featured patients with AAD, and collectively contained the data of 2,810 patients, and 6 featured patients with CDD, and collectively contained data on 354 patients. Meta-analysis revealed that probiotics had a significant protective effect for the development of AAD (relative risk [RR] 0.43, 95% CI 0.31-0.58, P <0.001). In a further meta-analysis by probiotic strain, Saccharomyces boulardii (S. boulardii), Lactobacillus rhamnosus GG (L. rhamnosus GG), and a mixture of two strains of Lactobacilli showed significant efficacy for treating AAD (RR 0.34, 95% CI 0.26-0.52; P <0.0001; RR 0.31, 95% CI 0.13-0.72; P = 0.006; and RR 0.51, 95% CI 0.38-0.68; P <0.0001, respectively). Meta-analysis also revealed that probiotics had a significant protective effect for the development of CDD (RR =0.59, 95% CI 0.41-0.85; P = 0.005). S.boulardii was the only probiotic that showed a significant reduction in the recurrence of CDD. Overall, 24 trials reported no adverse events, and those that did reported minor adverse events, including thirst and constipation.

ConclusionS. boulardii, L. rhamnosus GG, and probiotic mixtures significantly reduced the development of AAD. S. boulardii significantly reduced the development of CDD.

CommentaryProbiotics feature in a number of commercially successful products and dietary supplements, which are widely available in pharmacies, drugstores, and even supermarkets. Many people consider probiotics to be natural, beneficial agents that can exert favorable effects on health. The intestinal tract is the main target of the action of probiotics, and probiotics are perceived to be especially effective in treating diarrhea. Scientists, however, are more cautious about this claim, mainly because of the plethora of probiotic-containing products that are available. In addition, some products do not even seem to contain what they claim.[1]

AAD is an important indication for probiotics, which can re-establish the unbalanced composition of intestinal microflora, enhance immune response, and clear pathogens from the host. Published studies in this setting vary greatly in terms of trial design, type and dose of probiotic, and duration of treatment and therefore sometimes yield contradictory and inconclusive results. The lack of definitive evidence about the efficacy and the safety of probiotics has hampered their acceptance and use as a treatment for AAD and CDD. Previous meta-analyses[2,3] have examined only a limited number of trials, and failed to emphasize possible publication bias or data heterogeneity.

In this article, McFarland reports an exhaustive meta-analysis of 31 carefully selected, good-quality trials involving 2,810 patients with AAD, and 354 patients with CDD, who were treated with probiotics. Two single probiotic strains—S. boulardii and L. rhamnosus GG—as well as mixtures of different types of Lactobacilli, showed significant efficacy in AAD. Only S. boulardii, however, proved to be effective in preventing recurrences of CDD.

The first take-home message from this paper is that probiotics do exert the therapeutic effects on AAD in clinical practice that were anticipated from a theoretical point of view. This is extremely important because clinicians now have scientific evidence of a therapeutic indication that had, so far, remained controversial. The second, equally important message is that, once again, probiotics are an extremely heterogeneous group of micro-organisms that are endowed with different properties and modes of action. The assumption that the therapeutic effects of a particular probiotic agent might be attributed to other similar strains, or to the whole probiotic family, is totally wrong. Each agent must be tested and evaluated separately; admittedly, this is a time-consuming process, but it is the only way to obtain scientific evidence. Similarly, the efficacy of a probiotic in a specific disorder (e.g. AAD) does not automatically mean that the particular product will also be beneficial in other intestinal conditions (e.g. IBD or IBS), and vice versa. Finally, physicians must bear in mind that probiotics do not consist of only or mainly Lactobacilli. One of the few probiotic agents that have been proved to be effective in AAD, and the only one able to prevent CDD recurrence, is S. boulardii. This probiotic is a nonpathogenic yeast that, incidentally, has shown promising preliminary results as a supportive measure in the treatment of IBD.[4,5]

Practice point

Probiotics are effective for treating antibiotic-associated diarrhea and Clostridum difficile disease; Lactobacillus rhamnosus GG is effective for antibiotic-associated diarrhea, Saccharomyces boulardii is effective for both

The synopsis was written by Rachel Jones, Associate Editor, Nature Clinical Practice.

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